14-3-3σ positively regulates p53 and suppresses tumor growth

The 14-3-3sigma (sigma) protein, a negative regulator of the cell cycle, is a human mammary epithelium-specific marker that is downregulated in transformed mammary carcinoma cells. It has also been identified as a p53-inducible gene product involved in cell cycle checkpoint control after DNA damage. Although 14-3-3sigma is linked to p53-regulated cell cycle checkpoint control, detailed mechanisms of how cell cycle regulation occurs remain unclear. Decreased expression of 14-3-3sigma was recently reported in several types of carcinomas, further suggesting that the negative regulatory role of 14-3-3sigma in the cell cycle is compromised during tumorigenesis. However, this possible tumor-suppressive role of 14-3-3sigma has not yet been characterized. Here, we studied the link between 14-3-3sigma activities and p53 regulation. We found that 14-3-3sigma interacted with p53 in response to the DNA-damaging agent adriamycin. Importantly, 14-3-3sigma expression led to stabilized expression of p53. In studying the molecular mechanism of this increased stabilization of p53, we found that 14-3-3sigma antagonized the biological functions of Mdm2 by blocking Mdm2-mediated p53 ubiquitination and nuclear export. In addition, we found that 14-3-3sigma facilitated the oligomerization of p53 and enhanced p53's transcriptional activity. As a target gene of p53, 14-3-3sigma appears to have a positive feedback effect on p53 activity. Significantly, we also showed that overexpression of 14-3-3sigma inhibited oncogene-activated tumorigenicity in a tetracycline-regulated 14-3-3sigma system. These results defined an important p53 regulatory loop and suggested that 14-3-3sigma expression can be considered for therapeutic intervention in cancers.